This invention relates to a method for preventing visceral and gastrointestinal damage such as gastric ulcers by administering a gamma-aminobutyric acid (GABA) analog, and for treating gastrointestinal diseases such as inflammatory bowel disorders (IBD), functional bowel disorders (FBD), including dyspepsia and other visceral pain.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most frequently prescribed drugs for the treatment of pain associated with osteoarthritis and many other musculoskeletal and inflammatory disorders. In the United States, about 100 million prescriptions are written each year to provide effective relief of pain and treatment of inflammatory diseases. Commonly used NSAIDs include sulindac, naproxen, indomethacin, mefenamic acid, diclofenac, fenoprofen, and diflunisal.
However, considerable evidence indicates that NSAIDs have frequent, serious, and costly gastrointestinal tract toxic side effects. These include mild dyspepsia, gastritis, peptic ulcer disease, as well as more serious gastrointestinal complications such as bleeding and perforation, leading sometimes to significant morbidity and, to a lesser extent, mortality. Serious GI complications due to NSAID use represent the greatest threat to life in patients with connective tissue diseases, second only to the primary disease and its complications. Similar gastrointestinal damage is caused by ingestion of alcohol. Indeed, a condition known as ethanol withdrawal syndrome is commonly encountered when prolonged ethanol consumption is terminated. In addition to gastrointestinal damage, this syndrome often results in tremors, anxiety, convulsions, hallucinations, and confusion.
Other commonly encountered gastrointestinal disorders include inflammatory bowel disorders (IBD) and functional bowel disorders (FBD), including dyspepsia. These GI disorders include a wide range of disease states that are currently only moderately controlled, including Crohn""s disease, ileitis, ischemic bowel disease, and ulcerative colitis, as well as IBD, the irritable bowel syndrome, dyspepsia, and gastro-esophageal reflux for FBD, and other forms of visceral pain.
Gamma-aminobutyric acid has been shown to activate gastric afferent nerves which, in turn, have been shown to participate in gastric defense mechanisms. We have now discovered that GABA analogs dramatically reduce the gastrointestinal damage caused by drugs and alcohol. The GABA analogs also treat the conditions resulting from ethanol withdrawal syndrome, and GI disorders characterized as IBD and IBS.
All that is required to prevent gastrointestinal damage and to treat IBD, IBS, and alcoholism according to this invention is to administer to a subject who is in need of treatment an effective amount of a GABA analog.
Several GABA analogs are known. Gabapentin, a cyclic GABA analog, is now commercially available and extensively used clinically for treatment of epilepsy and neuropathic pain. Such compounds are described in U.S. Pat. No. 4,024,175. Another series of GABA analogs which are anti-seizure agents is described in U.S. Pat. No. 5,563,175.
This invention provides a method for preventing and treating gastrointestinal damage and disorders comprising administering to a subject in need of treatment an effective amount of a GABA analog. A preferred embodiment utilizes a cyclic amino acid compound of Formula I 
wherein R1 is hydrogen or lower alkyl and n is an integer of from 4 to 6, and the pharmaceutically acceptable salts thereof. An especially preferred embodiment utilizes a compound of Formula I where R1 is hydrogen and n is 5, which compound is 1-(aminomethyl)-cyclohexane acetic acid, known generically as gabapentin. Other preferred GABA analogs have Formula I wherein the cyclic ring is substituted, for example with alkyl such as methyl or ethyl. Typical compounds include (1-aminomethyl-3-methylcyclohexyl)acetic acid, (1-aminomethyl-3-methylcyclopentyl)acetic acid, and (1-aminomethyl-3,4-dimethylcyclopentyl)acetic acid.
In another embodiment, the method of the invention utilizes a GABA analog of Formula II 
or a pharmaceutically acceptable salt thereof, wherein
R1 is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl of from 3 to 6 carbon atoms;
R2 is hydrogen or methyl; and
R3 is hydrogen, methyl, or carboxyl.
Diastereomers and enantiomers of compounds of Formula II can be utilized in the invention.
An especially preferred method of the invention employs a compound of Formula II where R2 and R3 are both hydrogen, and R1 is xe2x80x94(CH2)0-2-i C4H9 as an (R), (S), or (R,S) isomer.
A more preferred embodiment of the invention utilizes 3-aminomethyl-5-methyl-hexanoic acid, and especially (S)-3-(aminomethyl)-5-methylhexanoic acid, now known generically as pregabalin, as well as CI-1008. Another preferred compound is 3-(1-aminoethyl)-5-methylhexanoic acid.
The invention additionally provides a composition comprised of an anti-inflammatory amount of an NSAID and a cytoprotective amount of a GABA analog.
As noted above, the method of this invention utilizes any GABA analog. A GABA analog is any compound derived from or based upon gamma-aminobutyric acid. The compounds are readily available, either commercially, or by synthetic methodology well-known to those skilled in the art of organic chemistry. The preferred GABA analogs to be utilized in the method of this invention are cyclic amino acids of Formula I. These are described in U.S. Pat. No. 4,024,175, which is incorporated herein by reference. Another preferred method utilizes the GABA analogs of Formula II, and these are described in U.S. Pat. No. 5,563,175 which is incorporated herein by reference.
All that is required to practice the method of preventing and treating gastrointestinal damage and disorders of this invention is to administer a GABA analog in an amount that is effective to prevent or treat the damage condition, i.e., to combat the effects of a NSAID or alcohol, or to control IBD and IBS. The invention includes a method for treating ethanol withdrawal syndrome and general alcoholism. The effective amount of GABA analog to be utilized will generally be from about 1 to about 300 mg per kg of subject body weight. Typical doses will be from about 10 to about 5000 mg per day for an adult subject of normal weight.
Typical xe2x80x9cgastrointestinal damagexe2x80x9d conditions caused by NSAID use include dyspepsia, gastritis, peptic ulcer, as well as lower gastrointestinal bleeding and perforation. Further effects of ethanol withdrawal syndrome include tremor, anxiety, and convulsions. Typical IBD conditions include ileitis, ulcerative colitis, and Crohn""s disease.
Pharmaceutical compositions of the compound of the present invention or its salts are produced by formulating the active compound in dosage unit form with a pharmaceutical carrier. Some examples of dosage unit forms are tablets, capsules, pills, powders, aqueous and nonaqueous oral solutions and suspensions, and parenteral solutions packaged in containers containing either one or some larger number of dosage units and capable of being subdivided into individual doses. Some examples of suitable pharmaceutical carriers, including pharmaceutical diluents, are gelatin capsules; sugars such as lactose and sucrose; starches such as corn starch and potato starch, cellulose derivatives such as sodium carboxymethyl cellulose, ethyl cellulose, methyl cellulose, and cellulose acetate phthalate; gelatin; talc; stearic acid; magnesium stearate; vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and oil of theobroma; propylene glycol, glycerin; sorbitol; polyethylene glycol; water; agar; alginic acid; isotonic saline, and phosphate buffer solutions; as well as other compatible substances normally used in pharmaceutical formulations. The compositions of the invention can also contain other components such as coloring agents, flavoring agents, and/or preservatives. These materials, if present, are usually used in relatively small amounts. The compositions can, if desired, also contain other therapeutic agents. For use in combating the gastrointestinal effects of NSAIDs, the GABA analogs can be administered alone in unit dosage form, or in combination with the NSAID being utilized for the particular patient.
The percentage of the active ingredient in the foregoing compositions can be varied within wide limits, but for practical purposes it is preferably present in a concentration of at least 10% in a solid composition and at least 2% in a primary liquid composition. The most satisfactory compositions are those in which a much higher proportion of the active ingredient is present, for example, from 10% to 90% by weight.
Routes of administration of the subject compound or its salts are oral or parenteral. For example, a useful intravenous dose is between 5 and 50 mg and a useful oral dosage is between 20 and 800 mg. The dosage is within the dosing range used in treatment of gastrointestinal diseases such as ulcers and IBS, or as would be dictated by the needs of the patient as described by the physician.
A unit dosage form of the GABA analog to be used in this invention may also comprise other compounds useful in the therapy of gastrointestinal diseases.
The advantages of using the compounds of Formula I and II, especially gabapentin and pregabalin, in the instant invention include the relatively nontoxic nature of the compounds, the ease of preparation, the fact that the compounds are well-tolerated, and the ease of IV and oral administration of the drugs. Further, the drugs are not metabolized in the body to any great extent.
The subjects as used herein are mammals, including humans.
The invention also provides a composition comprising an NSAID (non-steroidal anti-inflammatory drug) together with a GABA analog. The NSAID will be present in an anti-inflammatory amount, preferably somewhat less than normally used, and the GABA analog will be present in a cytoprotective amount, namely an amount which will be effective in preventing or reducing the gastrointestinal damage otherwise caused by the NSAID. In general, the NSAID will be present for doses of about 10 to about 500 mg, and the GABA analog will be present at about 1 to about 1500 mg. Any NSAID can be combined with any GABA analog according to this invention. Preferred GABA analogs to be employed are the compounds of Formulas I and II, especially gabapentin and pregabalin. Preferred NSAIDs to be employed in the compositions include sulindac, naproxen, indomethacin, mefenamic acid, diclofenac, fenoprofen, diflunisal, etodolac, ibuprofen, piroxicam, acetylsalicylic acid, oxaprozin, and bromfenac. Most of the NSAIDs to be used are commercially available, generally as salts such as calcium, sodium, or potassium, for example, fensprofen calcium and bromfenac sodium. Especially preferred combinations include pregabalin or gabapentin, together with naproxen sodium or ibuprofen. The compositions may contain common pharmaceutical excipients such as those described above.
The ability of GABA analogs to treat gastrointestinal diseases according to this invention has been established in several animal models of induced gastric lesions and alcoholism.